The present invention relates to compositions and methods for the treatment of Diabetes Mellitus. More specifically, the present invention relates to compositions to prolong the administration of glucagon-like peptide 1 (GLP-1), and derivatives thereof. These compositions are useful in treatment of Non-Insulin Dependent Diabetes Mellitus (NIDDM).
The amino acid sequence of GLP-1 is known as:
GLP-1 is disclosed by Lopez, L. C., et al., P.N.A.S., USA 80: 5485-5489 (1983); Bell, G. I., et al., Nature 302: 716-718 (1983); Heinrich, G. et al., Endocrinol. 115: 2176-2181 (1984) and Ghiglione, M., et al., Diabetologia 27: 599-600 (1984).
During processing in the pancreas and intestine, GLP-1 is converted to a 31 amino acid peptide having amino acids 7-37 of GLP-1, hereinafter this peptide is referred to as GLP-1 (7-37).
This peptide has been shown to have insulinotropic activity, that is, it is able to stimulate, or cause to be stimulated, the synthesis or expression of the hormone insulin. Because of this insulinotropic activity, GLP-1 (7-37) is alternatively referred to as insulinotropin.
GLP-1 (7-37) has the following amino acid sequence:
GLP-1 (7-37), certain derivatives thereof and the use thereof to treat Diabetes mellitus in a mammal are disclosed in U.S. Pat. Nos. 5,118,666 (""666 patent) and 5,120,712 (""712 patent), the disclosures of these patents being incorporated herein by reference. The derivatives of GLP-1 (7-37) disclosed in the ""666 and ""712 patents include polypeptides which contain or lack one of more amino acids that may not be present in the naturally occurring sequence. Further derivatives of GLP-1 (7-37) disclosed in the ""666 and ""712 patents include certain C-terminal salts, esters and amides where the salts and esters are defined as OM where M is a pharmaceutically acceptable cation or a lower (C1-C6) branched or unbranched alkyl group and the amides are defined as xe2x80x94NR2R3 where R2 and R3 are the same or different and are selected from the group consisting of hydrogen and a lower (C1-C6) branched or unbranched alkyl group.
Certain other polypeptides, alternatively referred to as truncated GLP-1 or truncated insulinotropin, having insulinotropic activity and the derivatives thereof are disclosed in PCT/US 89/01121 (WO 90/11296). Those polypeptides, referred to therein as GLP-1 (7-36), GLP-1 (7-35) and GLP-1 (7-34) have the following amino acid sequences, respectively.
Derivatives of the polypeptides disclosed in PCT/US89/01121 include polypeptides having inconsequential amino acid substitutions, or additional amino acids to enhance coupling to carrier protein or to enhance the insulinotropic effect thereof. Further derivatives of insulinotropin disclosed in PCT/US89/01121 include certain C-terminal salts, esters and amides where the salts and esters are defined as OM where M is a pharmaceutically acceptable cation or a lower branched or unbranched alkyl group and the amides are defined as xe2x80x94NR2R3 where R2 and R3 are the same or different and are selected from the group consisting of hydrogen and a lower branched or unbranched alkyl group.